Biological Efficacy and Safety of Niacinamide in Patients With ADPKD

Abstract

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst enlargement, leading to kidney failure. Sirtuin-1 is upregulated in ADPKD and accelerates disease progression by deacetylating p53. Niacinamide is a dietary supplement that inhibits sirtuins at high doses.

Methods: We conducted an open-label, single-arm intervention trial (study 1, N = 10), and a randomized, double blinded, placebo-controlled trial (study 2, N = 36) to assess the biological activity and safety of niacinamide. Patients with ADPKD were given 30 mg/kg oral niacinamide or placebo, for 12 months. The primary endpoint was the ratio of acetylated p53 to total p53 protein in peripheral blood mononuclear cells (PBMCs).

Results: There was no sustained effect of niacinamide on acetylated/total p53 in either study and no difference between placebo and niacinamide arms. There was no difference in the change in height-adjusted total kidney volume over 12 months between niacinamide and placebo. Niacinamide was generally well tolerated. The most common adverse effects were nausea, diarrhea, gastroesophageal reflux, headache, and acneiform rash but there was no difference in their incidence between niacinamide and placebo.

Conclusions: In conclusion, niacinamide is safe and well-tolerated in patients with ADPKD. However, we were unable to detect a sustained inhibition of sirtuin activity over 12 months of treatment, and there was no signal to suggest a beneficial effect on any efficacy measure.

Keywords: clinical trial; niacinamide; p53; polycystic kidney disease; sirtuin.

Graphical abstract

Figure 1

CONSORT flow diagram showing numbers of patients screened, enrolled, completed, and available for analysis of outcomes. htTKV, height-adjusted total kidney volume.

Figure 2

Ratio of acetyl-p53 to total p53 determined by Western blotting in peripheral blood mononuclear cells over the course of the study. (a) Values at each time point in study 1. ∗P = 0.003 for pairwise comparison to baseline values. (b) Values in each treatment arm at each time point in study 2. No difference between groups with respect to time or treatment arm was detected.